Nakanishi Kengo, Takamura Yoshihiro, Nakano Yusei, Inatani Masaru, Oki Masaya
Department of Industrial Creation Engineering, Graduate School of Engineering, University of Fukui, Fukui, Japan.
Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Genes Cells. 2025 Mar;30(2):e13196. doi: 10.1111/gtc.13196.
Retinal ischemic disease results in significant visual impairment due to the development of fragile and disorganized, pathologically running blood vessels in the eye. Currently, the mainstay treatment for this disease is the intravitreal administration of anti-VEGF drugs targeting vascular endothelial growth factor (VEGF), which induces angiogenesis. However, current anti-VEGF drugs do not diminish the ischemic areas that lead to angiogenesis, making fundamental treatment challenging. Since retinopathy is an acquired disease caused by hypoxic stimulation from ischemia, we paid particular attention to histone acetylases. We conducted a drug screening experiment using a mouse model of oxygen-induced retinopathy (OIR), which replicates retinal ischemic disease, through the intraperitoneal administration of 17 distinct inhibitors targeting histone acetyltransferases (HAT). The results indicated that, among the 17 inhibitors, only ISOX-DUAL decreased neovascularization and ischemic regions. Furthermore, microarray analysis was conducted on the drug-treated samples to refine genes altered by the administration of ISOX-DUAL. There were 21 genes associated with angiogenesis, including Angpt2, Hmox1, Edn1, and Serpine1, exhibited upregulation in OIR mice and downregulation following treatment with ISOX-DUAL. Furthermore, STRING analysis confirmed that the aforementioned four genes are downstream factors of hypoxia-inducible factors and are assumed to be important factors in retinal ischemic diseases.
视网膜缺血性疾病会导致严重的视力损害，这是由于眼部出现脆弱且紊乱、病理走行的血管所致。目前，该疾病的主要治疗方法是玻璃体内注射针对血管内皮生长因子（VEGF）的抗VEGF药物，VEGF可诱导血管生成。然而，目前的抗VEGF药物并不能减少导致血管生成的缺血区域，这使得根本性治疗颇具挑战性。由于视网膜病变是一种由缺血引起的缺氧刺激导致的后天性疾病，我们特别关注了组蛋白乙酰化酶。我们使用氧诱导视网膜病变（OIR）小鼠模型进行了药物筛选实验，该模型可复制视网膜缺血性疾病，通过腹腔注射17种针对组蛋白乙酰转移酶（HAT）的不同抑制剂来进行实验。结果表明，在这17种抑制剂中，只有ISOX-DUAL能减少新生血管形成和缺血区域。此外，对药物处理后的样本进行了微阵列分析，以筛选出因ISOX-DUAL给药而改变的基因。有21个与血管生成相关的基因，包括血管生成素2（Angpt2）、血红素加氧酶1（Hmox1）、内皮素1（Edn1）和丝氨酸蛋白酶抑制剂1（Serpine1），在OIR小鼠中上调，而在用ISOX-DUAL治疗后下调。此外，STRING分析证实上述四个基因是缺氧诱导因子的下游因子，被认为是视网膜缺血性疾病中的重要因子。
